TBI is a significant problem in developed countries. In the USA each year about 500,000 head injuries are severe enough to require hospitalization. Mortality is high and approximately 80,000 of these TBI-patients face a life-long debilitating loss of function, 5,000 develop epilepsy, and 2,000 live in a persistent vegetative state. TBI is the leading cause of death and disability in young adults today at an estimated cost in 1989 of over $25 billion per year.
Primary irreversible damage after brain trauma includes hemorrhage, contusion, neuronal necrosis and diffuse axonal injury. This damage, together with possible cardiovascular and respiratory depression, can induce acute secondary features including edema (vasogenic and/or cellular), secondary bleeding, alterations of cerebral blood volume (CBV), disturbed autoregulation of cerebral blood flow (CBF) and ischaemia. Edema, bleeding and an increase of CBV will increase the total brain volume and consequently the intracranial pressure (ICP). This in turn can lead to further progression of ischaemia, infarction, and, in severe cases, herniation of the brain stem with possible acute respiratory depression and death. Therapy in TBI should therefore be directed to the interruption of the pathologic cascade and the reduction of the brain volume and ICP. Prevention of a life threatening secondary increase in ICP, which often occurs e.g. in the post-acute phase after trauma or after cardiac resuscitation, is also a target for pharmacological treatment.
At present, the clinical tools for ICP reduction are limited. Standard treatment schedules include surgical drainage of the ventricles, blood pressure management, mannitol infusion, hyperventilation and high dose barbiturate therapy. Side effects of the non-surgical treatments include brain ischaemia, rebound effects on ICP and an increased risk for bacterial infections and sepsis. Also, various compounds with different mechanisms of actions (e.g. bradykinin antagonism, calcium antagonism, oxidative stress inhibition, glutamate receptor blockade and anti-epilepsy) have been tested in phase II and III clinical trials or are still under investigation (focus on outcome, not on ICP). Up to date no compound has been approved for the acute treatment of intracranial pressure (K. K. Jain, Chapter 4: Neuroprotection in Acute Trauma, ‘Neuroprotection in CNS Disorders: Commercial Opportunities’. A Jain PharmaBiotech Report: 65-73, 2000). Obviously, there is a need for pharmaceuticals and/or therapies for the treatment of elevated intracranial pressure (ICP) and/or secondary ischaemia, in particular caused by brain injury, more in particular caused by traumatic brain injury (TBI).
The purpose of the present invention is to provide novel substituted tetracyclic imidazole derivatives having the property of acutely lowering a critically elevated intracranial pressure (ICP) and thereby preventing e.g. secondary ischaemia caused by brain injury.
WO 88/05306 (The General Hospital Corporation) discloses treating cranial fluid volume dysfunctions such as edema, hydrocephalus or glaucoma in an individual with compounds which are interactive with the atriopeptin receptors, or other nitrogen-containing guanylate cyclase activators, or compounds which are phosphodiesterase inhibitors.
WO 92/06981 (Schering Corporation) discloses substituted tricyclic imidazobenzazepine and imidazopyridoazepine derivatives having antiallergic and/or anti-inflammatory activity; the compounds posses PAF antagonistic properties and are useful for treating diseases when PAF is a factor in the disease, such as e.g. edema.
WO 92/22551 (Janssen Pharmaceutica) discloses substituted tricyclic imidazo-[2,1-b][3]benzazepine derivatives having a favourable antiallergic/antihistaminic activity.
WO 92/22553 (Janssen Pharmaceutica) discloses substituted tricyclic imidazo[1,2-a](pyrrolo, thieno or furano)[3,2-d]azepine derivatives having a favourable antiallergic/antihistaminic activity.
WO 94/13671 (Janssen Pharmaceutica) discloses substituted tricyclic triazolobenzazepine derivatives having antiallergic/antihistaminic activity.
WO 94/13680 (Janssen Pharmaceutica) discloses substituted tricyclic imidazo[1,2-a](pyrrolo, thieno or furano)[3,2-d]azepine derivatives having a favourable antiallergic/antihistaminic activity.
WO 94/13681 (Janssen Pharmaceutica) discloses substituted tricyclic triazolo(pyrrolo, thieno or furano)azepine derivatives having antiallergic/antihistaminic activity.
WO 95/02600 (Janssen Pharmaceutica) discloses substituted tricyclic imidazoazepines with favourable antiallergic properties.
WO 97/24356 (Janssen Pharmaceutica) discloses 1-(1,2-disubstituted piperidinyl)-4(fused imidazole)-piperidine derivatives for use as substance-P antagonists.
WO 97/34897 (Janssen Pharmaceutica) discloses substituted tricyclic fused imidazole derivatives as multidrug resistance modulators.
WO 99/13871 ((Janssen Pharmaceutica) discloses fused imidazole derivatives for improving oral bioavailability of pharmaceutical agents.
None of the above publications discloses the compounds according to the present invention and their use for acutely lowering a critically elevated intracranial pressure (ICP).